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Ultra High Throughput Sequencing in Human DNA Variation Detection: A Comparative Study on the NDUFA3-PRPF31 Region
Paola Benaglio,Carlo Rivolta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013071
Abstract: Ultra high throughput sequencing (UHTS) technologies find an important application in targeted resequencing of candidate genes or of genomic intervals from genetic association studies. Despite the extraordinary power of these new methods, they are still rarely used in routine analysis of human genomic variants, in part because of the absence of specific standard procedures. The aim of this work is to provide human molecular geneticists with a tool to evaluate the best UHTS methodology for efficiently detecting DNA changes, from common SNPs to rare mutations.
Genes Associated with Retinitis Pigmentosa and Allied Diseases Are Frequently Mutated in the General Population
Koji M. Nishiguchi, Carlo Rivolta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041902
Abstract: Background Retinitis pigmentosa and other hereditary retinal degenerations (HRD) are rare genetic diseases leading to progressive blindness. Recessive HRD are caused by mutations in more than 100 different genes. Laws of population genetics predict that, on a purely theoretical ground, such a high number of genes should translate into an extremely elevated frequency of unaffected carriers of mutations. In this study we estimate the proportion of these individuals within the general population, via the analyses of data from whole-genome sequencing. Methodology/Principal Findings We screened complete and high-quality genome sequences from 46 control individuals from various world populations for HRD mutations, using bioinformatic tools developed in-house. All mutations detected in silico were validated by Sanger sequencing. We identified clear-cut, null recessive HRD mutations in 10 out of the 46 unaffected individuals analyzed (~22%). Conclusions/Significance Based on our data, approximately one in 4–5 individuals from the general population may be a carrier of null mutations that are responsible for HRD. This would be the highest mutation carrier frequency so far measured for a class of Mendelian disorders, especially considering that missenses and other forms of pathogenic changes were not included in our assessment. Among other things, our results indicate that the risk for a consanguineous couple of generating a child with a blinding disease is particularly high, compared to other genetic conditions.
CNOT3 Is a Modifier of PRPF31 Mutations in Retinitis Pigmentosa with Incomplete Penetrance
Giulia Venturini,Anna M. Rose,Amna Z. Shah,Shomi S. Bhattacharya,Carlo Rivolta
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003040
Abstract: Heterozygous mutations in the PRPF31 gene cause autosomal dominant retinitis pigmentosa (adRP), a hereditary disorder leading to progressive blindness. In some cases, such mutations display incomplete penetrance, implying that certain carriers develop retinal degeneration while others have no symptoms at all. Asymptomatic carriers are protected from the disease by a higher than average expression of the PRPF31 allele that is not mutated, mainly through the action of an unknown modifier gene mapping to chromosome 19q13.4. We investigated a large family with adRP segregating an 11-bp deletion in PRPF31. The analysis of cell lines derived from asymptomatic and affected individuals revealed that the expression of only one gene among a number of candidates within the 19q13.4 interval significantly correlated with that of PRPF31, both at the mRNA and protein levels, and according to an inverse relationship. This gene was CNOT3, encoding a subunit of the Ccr4-not transcription complex. In cultured cells, siRNA–mediated silencing of CNOT3 provoked an increase in PRPF31 expression, confirming a repressive nature of CNOT3 on PRPF31. Furthermore, chromatin immunoprecipitation revealed that CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression. In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31 transcripts to be produced and preventing manifestation of retinal degeneration.
Molecular Genetics of FAM161A in North American Patients with Early-Onset Retinitis Pigmentosa
Giulia Venturini, Silvio Alessandro Di Gioia, Shyana Harper, Carol Weigel-DiFranco, Carlo Rivolta, Eliot L. Berson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092479
Abstract: Retinitis pigmentosa (RP) is a hereditary disease that leads to the progressive degeneration of retinal photoreceptor cells and to blindness. It is caused by mutations in several distinct genes, including the ciliary gene FAM161A, which is associated with a recessive form of this disorder. Recent investigations have revealed that defects in FAM161A represent a rather prevalent cause of hereditary blindness in Israel and the Palestinian territories, whereas they seem to be rarely present within patients from Germany. Genetic or clinical data are currently not available for other countries. In this work, we screened a cohort of patients with recessive RP from North America to determine the frequency of FAM161A mutations in this ethnically-mixed population and to assess the phenotype of positive cases. Out of 273 unrelated patients, only 3 subjects had defects in FAM161A. A fourth positive patient, the sister of one of these index cases, was also identified following pedigree analysis. They were all homozygous for the p.T452Sfx3 mutation, which was previously reported as a founder DNA variant in the Israeli and Palestinian populations. Analysis of cultured lymphoblasts from patients revealed that mutant FAM161A transcripts were actively degraded by nonsense-mediated mRNA decay. Electroretinographic testing showed 30 Hz cone flicker responses in the range of 0.10 to 0.60 microvolts in all cases at their first visit (age 12 to 23) (lower norm = 50 μV) and of 0.06 to 0.32 microvolts at their most recent examination (age 27 to 43), revealing an early-onset of this progressive disease. Our data indicate that mutations in FAM161A are responsible for 1% of recessive RP cases in North America, similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. We also show that, at the molecular level, the disease is likely caused by FAM161A protein deficiency.
Accumulative Difference Image Protocol for Particle Tracking in Fluorescence Microscopy Tested in Mouse Lymphonodes
Carlo E. Villa,Michele Caccia,Laura Sironi,Laura D'Alfonso,Maddalena Collini,Ilaria Rivolta,Giuseppe Miserocchi,Tatiana Gorletta,Ivan Zanoni,Francesca Granucci,Giuseppe Chirico
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012216
Abstract: The basic research in cell biology and in medical sciences makes large use of imaging tools mainly based on confocal fluorescence and, more recently, on non-linear excitation microscopy. Substantially the aim is the recognition of selected targets in the image and their tracking in time. We have developed a particle tracking algorithm optimized for low signal/noise images with a minimum set of requirements on the target size and with no a priori knowledge of the type of motion. The image segmentation, based on a combination of size sensitive filters, does not rely on edge detection and is tailored for targets acquired at low resolution as in most of the in-vivo studies. The particle tracking is performed by building, from a stack of Accumulative Difference Images, a single 2D image in which the motion of the whole set of the particles is coded in time by a color level. This algorithm, tested here on solid-lipid nanoparticles diffusing within cells and on lymphocytes diffusing in lymphonodes, appears to be particularly useful for the cellular and the in-vivo microscopy image processing in which few a priori assumption on the type, the extent and the variability of particle motions, can be done.
Exome Sequencing of Index Patients with Retinal Dystrophies as a Tool for Molecular Diagnosis
Marta Corton, Koji M. Nishiguchi, Almudena Avila-Fernández, Konstantinos Nikopoulos, Rosa Riveiro-Alvarez, Sorina D. Tatu, Carmen Ayuso, Carlo Rivolta
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065574
Abstract: Background Retinal dystrophies (RD) are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES) as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context. Methodology/Principal Findings We ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants (~50% novel mutations) in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases. Conclusions/Significance Despite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available.
Abandono y reutilización de sitios: La problemática de los contextos habitacionales en quebrada de Humahuaca
Rivolta,María Clara;
Estudios atacame?os , 2007, DOI: 10.4067/S0718-10432007000200003
Abstract: we discuss the processes of abandonment and reuse of the residential sectors in quebrada de humahuaca, and define their causes and the moments they took place at the regional level, by assessing enclosure variability conditions in a single site. within this framework, we studied banda de perchel, a domestic terrace site where where we excavated two contiguous enclosures, observing substantial differences in terms of reiterated use in the first, and only partial use in the second, as defined by the perimetrical wall.
Nuevos avances en las prospecciones arqueológicas en la Quebrada de los Cardones
Rivolta,Gustavo M.;
Cuadernos de la Facultad de Humanidades y Ciencias Sociales. Universidad Nacional de Jujuy , 2005,
Abstract: in this paper to be inform over the result of archaeology prospections realizated at the "los cardones" ravine, located in the east of yocavil valley, in the tucuman province. to be prospections sites belonging at the stage of the regional developments. was effect surveys architectonics and planoaltimetric of the totality structures of one site the residential use, called los cardones, to be find summoned in the slopes and top of one hill, located in the left bank of amaicha river. were prospections the extensive cones footmountains until the low sectors near in the right bank of amaicha river, and to be documentated the structures, agricultural basicament, that ocupated different places on landscape. the abundant information collected permit to infer the articulation and organization the spase in the ravine, elaborated hypothesis over the differential utilization the distintc bounds in the zone of study. the model proposals classify the tipes of the structures, yours functionality possibles, the characteristic of the lanscape in that to be encounter seateds and your relations with the resources.
Abandono y reutilización de sitios: La problemática de los contextos habitacionales en quebrada de Humahuaca
María Clara Rivolta
Estudios Atacame?os , 2007,
Abstract: Se discuten los procesos de abandono y reutilización en sectores residenciales de quebrada de Humahuaca (Jujuy, Argentina), definiendo las causas y los momentos en los que estos procesos tuvieron lugar a nivel regional, así como la variación en las condiciones que pueden presentar los contextos habitacionales en un mismo sitio. De acuerdo a esto, consideramos el caso de las terrazas domésticas de Banda de Perchel, en el cual se efectuaron excavaciones en dos recintos contiguos, observando diferencias sustanciales en términos de un uso reiterado en uno de los casos asociado a otro con utilización parcial del espacio, definido por el muro perimetral. We discuss the processes of abandonment and reuse of the residential sectors in quebrada de Humahuaca, and define their causes and the moments they took place at the regional level, by assessing enclosure variability conditions in a single site. Within this framework, we studied Banda de Perchel, a domestic terrace site where where we excavated two contiguous enclosures, observing substantial differences in terms of reiterated use in the first, and only partial use in the second, as defined by the perimetrical wall.
María Clara Rivolta,Rossana Elizabeth Ledesma
Andes , 2009,
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